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FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells

Oncogene volume 23, pages 7753–7760 (2004)Cite this article

Abstract

Tumors have developed several forms of resistance to receptor-induced cell death. Here, we show that malignant mesothelial (MM) cell lines as well as primary MM cells and normal mesothelial (NM) cells express Fas and TNF-related apoptosis-inducing ligand (TRAIL) receptors DR4 and DR5. We found that, although Fas expression levels are comparable, only MM cells are resistant to cell death. Furthermore, MM cells show resistance to TRAIL-induced apoptosis. Caspase-8 (FLICE) is not activated by death receptors triggering in malignant cells whereas it is well activated by nonreceptor stimuli, such as UV radiation. We found that FLIP (FLICE-Inhibitory Protein) is constitutively expressed in all MM cell lines and is more expressed in primary MM cells than in NM cells. Knockdown of FLIP expression in MM cell lines, by a FLIPsiRNA, re-established the normal response to apoptosis induced by Fas or DR4/DR5, which was blocked by pretreatment with the caspase-8 inhibitor z-IETD-fmk. These results indicate that MM cells develop an intrinsic resistance to apoptosis induced by death receptors upregulating the expression of the antiapoptotic protein c-FLIP.

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Acknowledgements

This work was supported by grants from the Associazione Italiana per la Ricerca contro il Cancro (AIRC), from the Polytechnic University of Marche Research Fund and from the Italian Department of Scientific Research to AP and MRR and by special Grant DLgs 502/92 from Italian Ministery of Health to MRR. AC is a FIRC fellowship holder. The authors thank Dr Roberto Testi for providing DX2 hybridoma and Dr Michael Freeman for technical assistance.

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Authors and Affiliations

  1. Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, 60100, Italy

    Maria Rita Rippo, Simona Moretti, Silvia Vescovi, Marco Tomasetti, Alfonso Catalano & Antonio Procopio

  2. Laboratory of Cytology, Italian National Research Center on Aging, Ancona, 8 60124, Italy

    Alfonso Catalano & Antonio Procopio

  3. Department of Anatomical Pathology, S Antonio and Biagio Hospital, Alessandria, 15100, Italy

    Sara Orecchia

  4. Pediatric Hospital G Salesi, Ancona, 60100, Italy

    Giuseppe Amici

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  1. Maria Rita Rippo
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  2. Simona Moretti
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Correspondence to Maria Rita Rippo.

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Rippo, M., Moretti, S., Vescovi, S. et al. FLIP overexpression inhibits death receptor-induced apoptosis in malignant mesothelial cells. Oncogene 23, 7753–7760 (2004). https://doi.org/10.1038/sj.onc.1208051

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